Depression, aging and brain inflammation: indications for sustainable treatment

[fvplayer src='https://www.lapislight.com/wp/wp-content/uploads/2013/05/Post-05161.flv' width=384 height=216 autoplay=false splash='https://www.lapislight.com/wp/wp-content/uploads/2013/05/JDM-for-FLV-logo1.png' splashend=show] Depression and aging, not only diminished cognitive function but the level of physiological competence throughout the body, have brain inflammation in common. This fact is of premiere importance when designing rational treatment plans for both depression and high functioning longevity. Consider an important paper just published in the journal Depression and Anxiety which the authors the association of major depression and suicidal ideation with inflammatory biomarkers:

"Patients with major depressive disorder (MDD) who attempt or complete suicide have elevated inflammation compared to nonsuicidal patients with MDD. However, greater severity of depression and the medical lethality of suicide attempts could account for such elevated inflammation in suicide attempters and suicide completers...To clarify, we measured inflammatory markers in patients with MDD with and without high levels of suicidal ideation and in nondepressed controls (N = 124). Levels of suicidal ideation, depression severity, and recent suicide attempts were assessed by structured clinical interviews. A composite score including the inflammatory markers tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) was used as an inflammatory index."

Their data showed a correlation supporting their striking conclusion:

"Patients with MDD and high suicidal ideation had significantly higher inflammatory index scores than both controls...Suicidal ideation may be uniquely associated with inflammation in depressed patients." 

We should bear in mind that these inflammatory cytokines and CRP are not specific for depression. Moreover, there is a strong association between psychological stress and trauma and inflammatory biomarkers. A study just published in Comprehensive Psychiatry adds to the body of evidence supporting the relationship between depression, inflammation and stress:

"Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients."

Their data showed a particular correlation between major depression with childhood trauma and inflammatory cytokines:

"Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression." 

Inflammatory cytokines come into play with bipolar disorder too as expressed in a paper published in Progress in Neuro-Psychopharmacology and Biological Psychiatry:

"An emerging body of evidence points to impairments in neuroplasticity, cell resilience and neuronal survival as the main neuropathological correlates of BD. It has been suggested that inflammatory cytokines, particularly TNF-α may play a critical role in this process."

They examined evidence suggesting that TNF-α may regulate brain cell loss related to bipolar disorder:

"Current evidence suggests that an increase in serum levels of TNF-α takes place during manic and depressive episodes."

And we'll see that it is crucial for clinicians to be aware of the central role played by nuclear factor kappa-beta (NF-kB) in driving inflammatory cytokines in the brain in both depression and aging. Men with depression and history of early life stress are featured in a study published in The American Journal of Psychiatry. They evaluated innate immune system activation following psychosocial stress in patients with major depression and increased early life stress by measuring plasma interleukin (IL)-6, lymphocyte subsets, and DNA binding of nuclear factor (NF)-kB in peripheral blood mononuclear cells in medically healthy male subjects with current major depression and increased early life stress and comparing them to nondepressed male comparison subjects before and after completion of a stress test. They found that...

"Trier Social Stress Test-induced increases in IL-6 and NF-κB DNA-binding were greater in major depression patients with increased early life stress and independently correlated with depression severity...Male major depression patients with increased early life stress exhibit enhanced inflammatory responsiveness to psychosocial stress, providing preliminary indication of a link between major depression, early life stress and adverse health outcomes in diseases associated with inflammation." 

Many reading this are aware that the proinflammatory cytokine IL-1β is a 'mother cytokine' in the inflammatory cascade involved in most autoimmune inflammation. The authors of a fascinating study published in PNAS (Proceedings of the National Academy of the Sciences of the USA) demonstrate that IL-1β impairs neurogenesis in the hippocampus of the adult brain. Bear in mind that the hippocampus is the primary locus for short-term memory and adrenal regulation, and is a therapeutic target in the treatment of depression. The authors state:

"The profound consequences of stress exposure, defined as disturbances of physiological homeostasis, include a detrimental impact on certain aspects of brain function. In particular, uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and posttraumatic stress disorders. Alterations at the cellular level in the hippocampus have been linked to the pathophysiology of stress-related mood disorders. Many studies demonstrate that stressful experiences suppress hippocampal neurogenesis, which could contribute to the hippocampal atrophy observed in depressed patients. In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress, and reduces or even reverses hippocampal atrophy. Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety with some exceptions."

By administering exogenous IL-1β they compiled in vivo and in vitro evidence that stress exerts its effects on the hippocampus through activation of IL-1β signaling:

"Here, we demonstrate an essential role for the proinflammatory cytokine IL-1β. Administration of IL-1β or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1β receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-κB signaling pathway. These findings demonstrate that IL-1β is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress." 

Now we move further into the clinically extremely important role of nuclear factor-κB (NF-κB) signaling in autoimmune and brain inflammation. In a study also published in PNAS the authors build on the earlier insights regarding IL-1β and note:

"Exposure to stress and depression can result in atrophy of limbic brain regions that control emotion and mood, including inhibition of neurogenesis in the adult hippocampus...A role for proinflammatory cytokines is supported by a recent report that IL-1β signaling is necessary and sufficient for the antineurogenic and behavioral effects of stress. One possible signaling cascade that could mediate the effects of IL-1β is NF-κB, which is activated by IL-1β and other cytokines both in peripheral immune cells and in the brain. Chronic stress enhances the activation of NF-κB in response to inflammatory stimuli, and social stress increases NF-κB signaling in healthy subjects and produces an exaggerated response in depressed patients...In the present study, we investigate the role of NF-κB in the cellular and behavioral responses to acute and chronic stress. The results demonstrate that the inhibition of neurogenesis by stress occurs via activation of NF-κB in NSCs and that stress-induced anhedonia, a core symptom of depression, is dependent on NF-κB."

Their conclusion points to NF-κB signaling as a particularly important therapeutic target, especially considering that there are natural agents that can help:

"Stress inhibition of neurogenesis in the adult hippocampus, which has been implicated in the prodepressive effects of stress, is blocked by administration of an inhibitor of NF-κB. Further analysis reveals that stress activates NF-κB signaling and decreases proliferation of neural stem-like cells but not early neural progenitor cells in the adult hippocampus. We also find that depressive-like behaviors caused by exposure to chronic stress are mediated by NF-κB signaling. Together, these data identify NF-κB signaling as a critical mediator of the antineurogenic and behavioral actions of stress and suggest previously undescribed therapeutical targets for depression." 

Then how fascinating is it that researchers publishing in The Journal of Neuroscience demonstrate that darkness (light deprivation), known to induce depression, does so through the NF-κB signaling pathway:

"Depression has been tightly linked to disturbances of circadian rhythms, and alterations in emotional states have been found to affect circadian rhythms. Seasonal affective disorders, a subtype of major depressive disorders related to seasonal variations in natural light levels, occur at higher prevalence in the more northern latitudes, in regions with extended periods of restricted sunlight...Disturbed day–night cycles and altered sleep patterns are also known to affect the rhythmic intradiem oscillations of elements of the immune system, such as IL-6. Interestingly, elevated inflammatory parameters, including IL-6, are also frequently observed in depressed patients...We therefore decided to use a particular case of circadian disruption, light deprivation in the DD paradigm, and to examine the potential involvement of inflammatory signaling in the associated depressive state."

Their data showed not only IL-6 activity, but that NF-κB signaling again plays a pivotal role in depression induced by light deprivation:

"We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression." 

And increased NF-κB pathway signaling is also reported in women suffering childhood abuse-related post-traumatic stress disorder in a study published in the journal Brain, Behavior, and Immunity:

"In addition to neuroendocrine changes PTSD pathophysiology may also involve dysfunction of the innate immune inflammatory system. PTSD patients have been found to exhibit increased concentrations of circulating inflammatory markers such as C-reactive protein and interleukin-6, suggesting dysfunction of the innate immune inflammatory system."

So the authors examined NF-κB activity obtained from 12 women with childhood abuse-related PTSD and 24 healthy controls. They also measured glucocorticoid sensitivity of monocytes in a clever wsy by observing the amount of dexamethasone needed to suppress lipopolysaccharide-induced tumor necrosis factor-alpha production by 50%. Sure enough, NF-κB was pivotal here too:

"Women with PTSD displayed increased NF-κB pathway activity compared to controls that was positively correlated with PTSD severity (determined by PTSD symptom severity scale). Increased NF-κB pathway activity was associated with increased whole blood monocyte DEX IC50 (i.e. decreased sensitivity of monocytes to glucocorticoids) across all participants."

In other words, the PTSD symptoms were promoted by immune inflammatory acitivity hinging on NF-κB signaling. The authors conclude:

"These findings suggest that enhanced inflammatory system activity in participants with childhood abuse-related PTSD is observable at the level of NF-κB, and that in general decreased immune cell glucocorticoid sensitivity may contribute to increased NF-κB pathway activity. Enhanced inflammation may contribute to co-morbid somatic disease risk in persons with childhood abuse-related PTSD." 

More evidence that NF-κB plays a key role in central nervous system inflammation is offered by a study published in the Journal of Neuroinflammation. The authors observe by way of background:

"Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system (CNS). The development of autoimmune diseases such as MS requires the coordinated expression of a number of pro-inflammatory genes. These factors...encompass a variety of cytokines, chemokines, adhesion molecules as well as other inflammatory factors...Nuclear factor (NF-) kappaB (NF-κB) is essential for both innate and adaptive immunity...and is involved in many inflammatory processes...The transcriptional activation of the NF-κB pathway is controlled by the inhibitor of NF-κB, IκB...Besides the involvement of NF-κB in T-cell proliferation and activation, it is also a key element in coordinately controlling gene expression during monocyte/macrophage activation. In particular the macrophage-derived cytokines interleukin-1beta (IL-1 β) and tumor necrosis factor-alpha (TNF-α), are potent activators of NF-κB. In turn, their expression is controlled by NF-κB thus resulting in a positive feedback loop. Hence, NF-κB signalling pathways may play a pivotal role in activating myeloid cell function during autoimmune inflammation. In addition to its central mediatory function in cytokine expression, NF-κB in myeloid cells may be induced by physical as well as oxidative stress to cells, e.g. via the inducible nitric oxide synthase (iNOS) or cyclooxygenase-2 (COX-2)."

The authors shed light on the role of NF-κB in CNS inflammation by examining experimental autoimmune encephalomyelitis (MOG-EAE, a well established experimental model for autoimmune demyelination of the CNS) in mice whose NF-κB inhibitor IκB was rendered genetically inactive. They found that...

"...loss of IκB in monocytes and macrophages leads to constitutive expression of NF-κB. In turn, this results in an increased expression of NF-κB regulated monocyte/macrophage cytokines and subsequently enhanced macrophage infiltration and iNOS expression in the spinal cord...Thus macrophage derived, NF-κB dependent cytokines may play a pivotal role in the pathogenesis of EAE and determine the outcome of autoimmune inflammation in the CNS without interfering with Th1 and Th17 T-cell responses. Our findings suggest that NF-κB in myeloid cells is a master regulator for regulation of inflammation and tissue damage in autoimmune inflammation of the CNS."

Consider how surprisingly decisive the NF-κB activity is since it determined the outcome of the autoimmune inflammation without modifying the Th17 response. These authors conclude:

"In summary, myeloid cell derived NF-κB plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells." 

T-helper (Th) 17 cells and the proinflammatory cytokine IL-17 are a 'common pathway' in autoimmunity. While the previous paper showed that NF-κB can drive autoimmune inflammation by other means as well, another study recently published in PNAS shows that NF-κB also promotes Th17 differentiation. The authors state:

"IL-17–producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor κB (NF-κB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial."

They used genetic models to demonstrate that NF-κB signaling controls survival and proliferation of activated T cells, and has an additional role in promoting completion of Th17 differentiation. Specifically the CARD-containing MAGUK protein 1 (CARMA1)is an adapter TCR/NF-κB signaling, resulting in the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6...

"Consistent with these data, CARMA1-KO [knockout] mice were resistant to experimental autoimmune encephalomyelitis...Our results demonstrate that TCR/CARMA1/NF-κB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci."

Moreover, NF-κB and pro-inflammatory cytokines contribute to major depression by altering glucocorticoid receptor function as presented in a paper published in the Annals of The New York Academy of Sciences:

"Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR)...Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR-DNA binding through nuclear protein-protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform."

Clinicians take note: this is an important dimension to consider in assessing HPA and adrenocortical function and cortisol effectiveness. Cortisol levels might be looking OK but not working properly. Regarding NF-κB:

"Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen-activated protein kinase...and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor-κB (NF-κB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-κB nuclear interactions."

Moreover...

"Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression." 

Inflammation in the hypothalamus drives aging throughout the body

To top it all off, there is emerging evidence that inflammation enacted by NF-κB in the brain, specifically the hypothalamus, drives many aspects of aging throughout the body. In what has been described as “a major breakthrough in ageing research”, by David Sinclair, a molecular biologist at Harvard Medical School, researchers publishing in the esteemed journal Nature reveal how...

"...the hypothalamus is important for the development of whole-body ageing in mice, and that the underlying basis involves hypothalamic immunity mediated by IκB kinase-β (IKK-β), nuclear factor κB (NF-κB) and related microglia–neuron immune crosstalk."

Using several models they were able to slow aging and extend lifespan by preventing aging-related hypothalamic or brain IKK-β and NF-κB activation. They also demonstrated that IKK-β and NF-κB inhibit gonadotropin-releasing hormone (GnRH), a 'master switch' hormone for the whole body, causing a decline in hypothalamic GnRH. Moreover, they showed that GnRH treatment ameliorated aging-impaired neurogenesis and slowed down aging. Commenting on this study, another author reporting in the same journal noted:

"The area of the brain that controls growth, reproduction and metabolism also kick-starts ageing...Dongsheng Cai, a physiologist at Albert Einstein College of Medicine in New York, and his colleagues tracked the activity of NF-κB...They found that the molecule becomes more active in the brain area called the hypothalamus as a mouse grows older...Further tests suggested that NF-κB activity helps to determine when mice display signs of ageing. Animals lived longer than normal when they were injected with a substance that inhibited the activity of NF-κB in immune cells called microglia in the hypothalamus. Mice that received a substance to stimulate the activity of NF-κB died earlier. “We have provided scientific evidence for the concept that systemic ageing is influenced by a particular tissue in the body,” says Cai."

David Cai, the lead author, also states:

"Inflammation involves hundreds of molecules, and NF-κB sits right at the center of that regulatory map...The mice showed a decrease in muscle strength and size, in skin thickness, and in their ability to learn — all indicators of aging. Activating this pathway promoted systemic aging that shortened the lifespan."

Also noted by David Sinclair:

"...a key finding is that blocking the effects of NF-κB produced anti-ageing effects even when it was done in middle age."

The authors state in their conclusion:

"...the hypothalamus has a programmatic role in ageing development via immune–neuroendocrine integration, and immune inhibition or GnRH restoration in the hypothalamus/brain represent two potential strategies for optimizing lifespan and combating ageing-related health problems."

And in another comment in the same edition of Nature:

"Inflammation-activated signalling pathways in the brain's hypothalamus control the production of ageing-related hormones. This finding provides a link between inflammation, stress responses and systemic ageing."

This installment presents a few drops from an ocean of science implicating brain inflammation as a key factor in cognitive and emotional disorders and global impairments in physiological competence, including loss of function associated with aging. Forthcoming posts will present studies demonstrating resources for sustainable treatment of NF-κB driven inflammation and autoimmunity.